Antiandrogenic compositions containing indene-7-ones

ABSTRACT

Novel antiandrogenic compositions comprising an antiandrogenically effective amount of at least one compound of the formula ##STR1## wherein R is alkyl of 1 to 4 carbon atoms, R 1  is alkyl of 1 to 2 carbon atoms, R 2  is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms optionally interrupted with a heteroatom, alkenyl and alkynyl of 2 to 8 carbon atoms optionally interrupted with a heteroatom, formyl and acyl of an organic carboxylic acid of 2 to 18 carbon atoms, R 3  is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms, R 4  is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, the dotted lines indicate optional presence of a double bond between the 4(5) and 5a(6) carbons and the wavy line indicates that R 4  may be in the α- or β-position and a non-toxic, pharmaceutical carrier or excipient and a method of treating hyperandrogenic conditions in warm-blooded animals.

PRIOR APPLICATION

This application is a continuation-in-part of our copending, commonlyassigned U.S. patent application Ser. No. 350.151 filed Feb. 19, 1982,now U.S. Pat. No. 4,466,971.

STATE OF THE ART

Some of the compounds of formula I are known such as those described inBelgium Pat. No. 663,197 and French Pat. No. 1,359,675 and J. Org.Chem., 1969, Vol. 34 (1), p. 107-112. Also pertinent is Swiss Pat. No.558,343 and European Patent Application Ser. No. 0014,966 and U.S. Pat.Nos. 3,984,473 and 3,984,474.

OBJECTS OF THE INVENTION

It is an object of the invention to provide novel antiandrogeniccompositions and a novel method of inducing antiandrogenic activity inwarm-blooded animals.

It is another object of the invention to provide novel compounds offormula I' and a novel process for their preparation.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel antiandrogenic compositions of the invention are comprised of##STR2## wherein R is alkyl of 1 to 4 carbon atoms, R₁ is alkyl of 1 to2 carbon atoms, R₂ is selected from the group consisting of hydrogen,alkyl of 1 to 8 carbon atoms optionally interrupted with a heteroatom,alkenyl and alkynyl of 2 to 8 carbon atoms optionally interrupted with aheteroatom, formyl and acyl of an organic carboxylic acid of 2 to 18carbon atoms, R₃ is selected from the group consisting of hydrogen,alkyl of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbonatoms, R₄ is selected from the group consisting of hydrogen and alkyl of1 to 4 carbon atoms, the dotted lines indicate optional presence of adouble bond between the 4(5) and 5a(6) carbons and the wavy lineindicates that R₄ may be in the α- or β-position and a non-toxicpharmaceutical carrier The compounds of formula I indicate products ofnatural series, racemic products and products of antipodal series.

Examples of R are methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl,tert.-butyl and isobutyl. Examples of R₂ are alkyl such as methyl,ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl, tert.-butyl,pentyl, sec-pentyl, isopentyl and linear or branched hexyl, heptyl andoctyl, alkenyl such as vinyl, allyl and butenyl and alkynyl such asethynyl, propynyl or butynyl.

When R₂ is alkyl, alkenyl or alkynyl interrupted by a heteroatom, R₂preferably has the formula

    --CH.sub.2 --A--(CH.sub.2).sub.n --CH.sub.3

wherein A is oxygen or sulfur and n is a number from 0 to 4.

R₂ in this instance is preferably methoxymethyl, lower alkoxymethyl suchas ethoxymethyl or methylthiomethyl.

Examples of suitable organic carboxylic acids of 2 to 18 carbon atomsfor the acyl of R₂ are optionally unsaturated aliphatic orcycloaliphatic carboxylic acids such as acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, hexanoic acid, pivaloicacid, undecanoic acid, acrylic acid, crotonic acid, cyclobutyric acid,cyclopropane carboxylic acid and cyclopentyl carboxylic acid;cycloalkanoic acids such as cyclopentylacetic acid, cyclopentylpropionicacid, cyclohexylacetic acid and cyclohexylpropionic acid; benzoic acids;phenylalkanoic acids such as phenylacetic acid and phenylpropionic acidand hetero containing acids such as 3-pyridinyl-carboxylic acid,4-pyridinyl-1-carboxylic acid, thiazolyl-carboxylic acid,4,5-dihydrothiazolyl-carboxylic acid, oxazolyl-carboxylic acid andimidazolylcarboxylic acid and alkanoic acids interrupted by a heteroatomsuch as methoxyacetic acid.

Examples of R₃ and R₄ as alkyl, alkenyl or alkynyl are the same groupsdiscussed above for R₂.

Among the preferred compositions of the invention are those wherein R ismethyl or ethyl, those wherein R₃ and R₄ are each hydrogen, thosewherein the dotted line in the 4(5) position is not a double bond, thosewherein the dotted line in the 5a(6) position is a double bond and thosewherein R₂ is hydrogen, methoxymethyl, allyl, acetyl or butyryl.Specific preferred compounds are3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3β-ol-7-one,3aβ,6-diethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3.beta.-ol-7-one,3aβ-methyl-3β-acetoxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-7-oneand3β-(pyridin-3-yl)-carbonyloxy-3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-7-one.

The compositions may be in the form of solutions, emulsions, creams,pomades, lotions, gelules, tablets, dragees, suppositories.

The compositions inhibit the effect of androgens on the level ofperipherial organs without interfering with normal hypophysialfunctions. They may be used to treat adolescents without fear ofarresting their growth and to treat adults without fear of certaineffects of chemical castration.

The compositions may be used for treatment of local affections due to ahyperandrogenicity such as acne, hirsutism, seborrhea, hyperpilosity,androgen-dependent hair loss especially male pattern baldness(alopecia). The compositions may also be used as deodorants,particullarly axillary deodorants. They may be in the usual form fortopical application or rectal or oral administration.

Preferably the compositions are administered topically.

Examples of suitable excipients are aqueous or nonaqueous vehicles,lactose, starch, fatty bodies of animal or vegetable origin, paraffinicderivatives, glycols, diverse wetting agents, dispersants or emulsifiersand preservatives. When administered orally or rectally, thecompositions are preferably gelules, tablets or suppositories.

When the compositions are applied topically, they are preferably in theform of an emulsion, cream, pomade or lotion containing 1 to 20%,preferably 2 to 10%, by weight of the compounds of formula I and it isapplied 1 to 5 times per day.

The novel method of the invention for treating hyperandrogenocity inwarm-blooded animals, including humans, comprises administering towarm-blooded animals an antiandrogenically effective amount of at leastone compound of formula I. The usual daily dose will vary on thecompound used, the condition treated and the method of administration.

The novel compounds of the invention have the formula ##STR3## whereinR, R₁, R₂, R₃ and R₄, the dotted line and the wavy line have the abovedefinition excluding the compounds wherein R₄ is hydrogen, the dottedline in the 4(5)-position is not a double bond and the dotted line inthe 5a(6)-position is a double bond and (a) R is methyl, R₃ is hydrogenand (i) R₂ is hydrogen, acetyl, tert.-butyl or benzoyl and R₁ is methylor (ii) R₂ is hydrogen or tert.-butyl and R₁ is ethyl, (b) R is ethyl orpropyl, R₃ is hydrogen, R₂ is hydrogen or benzoyl and R₁ is methyl, (c)R is butyl, R₁ is methyl, R₂ is hydrogen and R₃ is hydrogen, (d) R ismethyl, R₁ is methyl, R₂ is hydrogen and R₃ is methyl or ethyl andexcluding the compounds where-in R₄ is hydrogen and the dotted lines donot indicate a double bond and (a) R₁ and R are methyl, R₃ is hydrogenand R₂ is hydrogen, acetyl or benzoyl, (b) R and R₁ are methyl, R₂ ishydrogen and R₃ is ethyl, propargyl or isobutenyl, (c) R₃ is hydrogenand (i) R and R₁ are methyl and R₂ is methoxymethyl, (ii) R is ethyl, R₁is methyl and R₂ is hydrogen or (iii) R is methyl, R₁ is ethyl and R₂ ishydrogen and (d) R, R₁ and R₃ are methyl and R₂ is hydrogen or acetyl.

The preferred compounds of formula I' are those wherein R₄ is alkyl of 1to 4 carbon atoms, those wherein the dotted lines in the 4(5) and5a(6)-positions are double bonds and those wherein the dotted line inthe 5a(6)-position is a double bond and R and R₁ are ethyl. Specificpreferred compounds of formula I' are3aβ,6-diethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3.beta.-ol-7-one,3aβ-methyl-3β-acetoxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-oneand3β-(pyridin-3-yl)-carbonyloxy-3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one.

The process of the invention for the preparation of compounds of theformula ##STR4## wherein R and R₁ have the above definitions with theproviso that R is not methyl, ethyl, n-propyl or n-butyl when R₁ ismethyl and R is not methyl when R₁ is ethyl comprises reacting acompound of the formula ##STR5## with a compound of the formula

    R--CH.sub.2 --MgX                                          III.sub.A

wherein A is acyl of an organic carboxylic acid of 2 to 18 carbon atomsand X is a halogen and saponifying the resulting ester to obtain acompound of formula I_(A) '.

The process for the preparation of a compound of the formula ##STR6##wherein R and R₁ have the above definition and R₄ ' is alkyl of 1 to 4carbon atoms comprises reacting a compound of the formula ##STR7##wherein R and R₁ have the above definition with a ketone protectingreactant to obtain a compound of the formula ##STR8## wherein B is aketal, enamine or enol ether and the dotted line is a double bond when Bis an enamine or enol ether, reacting the latter with an oxidation agentto obtain a compound of the formula ##STR9## treating the latter with aniodide of the formula R₄ ' I in the presence of a strong base to form acompound of the formula ##STR10## reacting the latter with a reducingagent to obtain a compound of the formula ##STR11## and treating thelatter to remove the ketone protecting group to obtain the compound offormula I_(B) '.

The novel process of the invention for the preparation of a compound ofthe formula ##STR12## wherein R, R₁, R₃ and R₄ have the above definitionwith the proviso that when R₄ is hydrogen, R and R₁ are not methyl whenR₃ is ethyl comprises reacting a compound of the formula ##STR13##wherein B, R, R₁, R₄ and the dotted line have the above definition witha compound of the formula R₃ --D wherein R₃ has the above definition andD is lithium or Mg--Hal and Hal is a halogen to obtain a compound of theformula ##STR14## and treating the latter to remove the ketoneprotecting group to obtain the compound of formula I_(C) '.

The novel process of the invention for the preparation of a compound ofthe formula ##STR15## wherein R, R₁, R₃ and R₄ have the abovedefinitions comprises reacting a compound of the formula ##STR16## witha hydroxyl protecting reactant to obtain a compound of the formula##STR17## wherein A' is a hydroxyl protecting group, reacting the latterwith a brominating agent to obtain a compound of the formula ##STR18##and treating the latter with a dehydrobromination agent and an agent toremove the hydroxyl protecting group to obtain a compound of formulaI_(D) '.

The novel process of the invention for the preparation of a compound ofthe formula ##STR19## wherein R, R₁, R₃ and R₄ have the above definitionwith the proviso that when R₄ is hydrogen, (a) R and R₁ are not methylwhen R₃ is hydrogen, methyl, ethyl, propargyl or isobutenyl or (b) whenR₃ is hydrogen, R is not methyl and R₁ is ethyl or R₁ is methyl and R isnot ethyl comprises reacting a compound of the formula ##STR20## with ahydrogenation agent to obtain the compound of formula I_(E) '.

The novel process of the invention for the preparation of a compound ofthe formula ##STR21## wherein R, R₁, R₃, R₄ and the dotted lines havethe above definitions and R₂ ' is R₂ other than hydrogen excluding thecompounds wherein R₄ is hydrogen, the dotted line in the 4(5) positionis not a double bond and the dotted line in the 5a(6)-position is adouble bond and (a) R is methyl, R₃ is hydrogen and (i) R₂ ' is acetyl,tert.-butyl or benzoyl and R₁ is methyl or (ii) R₂ ' is tert.-butyl andR₁ is ethyl, (b) R is ethyl or propyl, R₃ is hydrogen, R₂ ' is benzoyland R₁ is methyl and excluding also the compounds wherein R₄ is hydrogenand the dotted lines do not indicate a double bond and (a) R₁ and R aremethyl, R₃ is hydrogen and R₂ ' is acetyl or benzoyl, (b) R and R₁ aremethyl, R₂ ' is methoxymethyl and R₃ is hydrogen and (c) R, R₁ and R₃are methyl and R₂ ' is acetyl comprising either reacting a compound ofthe formula ##STR22## with a compound of the formula R₂ '--E wherein Eis a functional group residue and R₂ ' has the above definition toobtain the corresponding compound of formula I_(F) ' or reacting acompound of the formula ##STR23## wherein B has the above definitionwith a compound of the formula R₂ '--E wherein R₂ ' and E have the abovedefinition to obtain a compound of the formula ##STR24## and treatingthe latter to remove the ketone protecting group to obtain a compound offormula I_(F) ' wherein there is no double bond in the 4(5)-position.

The condensation with the magnesium compound of formula III_(A) which ispreferably ethyl magnesium bromide is effected under the usualconditions for this type of reactant, preferably in an anhydrous organicsolvent such as ethyl ether or tetrahydrofuran at low temperatures onthe order of -50° C.

The saponification of the products is effected by treatment with a basesuch as sodium hydroxide, potassium hydroxide or baryta and the productmay be recovered by treatment with an acid such as hydrochloric acid,acetic acid or sulfuric acid. In the compounds of formula II_(A), A ispreferably acetyl.

The 7-ketone protective groups of the compounds of formula III_(B) arepreferably ethylene ketal or pyrrolidine enamine and methoxy or ethoxyenol ethers. The ketone protective reactant for reaction with thecompound of formula II_(B) in this case would be ethylene glycol,pyrrolidine, methanol or ethanol. The reaction with ethylene glycol ormonoalcohol is preferably effected in the presence of an acid such asp-toluene sulfonic acid.

The oxidation agent to react with the compound of formula III_(B) ispreferably pyridinium dichromate although other agents such assulfochromic acid solution, pyridinium chlorochromate, chromium trioxidein pyridine or an Oppenhauer oxidation agent such as aluminumisopropoxide or aluminum tert.-butoxide may be used.

The strong base used in the presence of the reaction of the compound offormula IV_(B) with R₄ --I is preferably a lithium amide, especiallylithium diisopropylamide formed in situ from butyllithium anddiisopropylamine. Also useful are other strong bases such as alkalimetal amides generally or alkali metal hydroxides such as sodiumhydride. The reduction of the compounds of formula V_(B) is preferablyeffected with lithium aluminum hydride although other hydrides such assodium borohydride or potassium borohydride or lithium borohydride maybe used.

The removal of the protective groups of formula V_(B) ' may be effectedby known means, especially by acid hydrolysis such as treatment withp-toluene sulfonic acid, hydrochloric acid or acetic acid.

The products of formulae V_(B) and V_(B) ' may occur in the form of 2α-or 2β-isomers or in a form of a mixture of the said isomers whichmixtures can be separated, if desired, by known methods such aschromatography. When only one of the isomers is obtained or ispredominantly obtained, the other isomer can generally be obtained byisomerization of the obtained sole isomer. The isomerization may beeffected by heating in a basic medium such as a potassium methanolatesolution and the resulting mixture may be separated by known methodssuch as chromatography. The isomerization or isomer separation ispreferably effected with the compounds of formula V_(B).

The magnesium derivative for reaction with a compound of formula II_(C)is preferably an alkyl magnesium bromide in an organic solvent such astetrahydrofuran or ether. The removal of the ketone protecting group iseffected as discussed above.

The hydroxyl protection of the compounds of formula II_(D) may beeffected in a known manner preferably by esterification as the acetylgroup by reaction with acetic anhydride but equally useful is protectionwith a tetrahydropyranyl group. The formation of the 4(5)-double bond ispreferably effected with N-bromosuccinimide followed by treatment with adehydrobromination agent such as pyridine, collidine or a mixture oflithium carbonate and lithium bromide.

The removal of the hydroxyl group is effected by known methods. When theprotection is effected by ester such as acetyl, the group is removed bythe saponification conditions described above. When the hydroxyl groupis protected by tetrahydropyranyl, it is removed by acid hydrolysisunder the usual conditions. The hydrogenation of the compounds offormula II_(E) ' is effected, for example, with hydrogen in the presenceof a catalyst such as platinum or platinum oxide.

The reactant, R₂ '--E, which is reacted with a compound of formulaeII_(F) or II_(F) ' is a halide of alkyl alkenyl or alkynyl optionallyinterrupted with a heteroatom. The halide is preferably chloride orbromide and the reaction is effected in the presence of an organic basesuch as triethylamine or a mineral base or basic salt such as sodiumbicarbonate, lithium bicarbonate or potassium bicarbonate.

The hydroxyl group may also be esterified by reaction with a mixed orsymmetrical anhydride such as acetic anhydride or butyric anhydride orwith an acyl halide such as acetyl chloride. The removal of theprotective group of formula III_(F) ' is effected as discussed above.

The preparation of the racemic products and the antipodal compounds iseffected in the same fashion beginning from the corresponding startingmaterials.

The starting compounds of formula II_(A) may be prepared by theprocesses of French Pat. No. 1,364,556 and No. 1,476,509. The startingproducts of formula II_(B) are partially a part of the compounds offormula I_(A) ' and may be prepared by the process of the applicationand the other compounds are described in J. Org. Soc., 1962, p.1312-1313; Helv. Chim. Acta. Vol. 54(7) (1971), p. 2121-2132; J. Org.Chem., Vol. 34(1) (1969), p. 107-112; French Pat. No. 1,359,675.

The starting compounds of formula II_(C) are partially within the scopeof formula V_(B) and may be prepared by the described process and thecompounds wherein R₄ is hydrogen are described in French Pat. No.1,553,958. The starting compounds of formula II_(D) are partially withinformula I_(C) ' and may be prepared accordingly and the other compoundsare known in Belgium Pat. No. 663,197. The compounds of formula II_(E) 'are within the scope of formula II_(D).

The starting products of formula II_(F) are described above and thestarting products of formula II_(F) ' are prepared in an analogousmanner to that for the compounds of formula III_(B) described above. Thesame process may be used for the starting compounds of formula II_(F)with a double bond lacking in the 4(5)-position.

The compounds of formula I which are not within the scope of formula I'which may be prepared by the process of the invention are known. Theymay be prepared by the processes mentioned hereinafter.

The compounds of formula I with a double bond in the 5a(6)-position andwherein R is methyl and R₃ is hydrogen may be prepared by the processesof French Pat. No. 1,359,675, J. Org. Chem., Vol. 34(5) (1969),p.1457-1458; Ann. Vol. 669 (1963), p. 153-159; J. Org. Chem., Vol. 34(1)(1969), p. 107-112 and German Application No. OLS 1,811,693. Thecompounds of formula I with a double bond in the 5a(6)-position andwherein R₃ is hydrogen and R is alkyl other than methyl may be preparedby the process of French Pat. No. 1,359,675 and Helv. Chim. Acta., Vol.54(7) (1971), p. 2121-2132.

The compounds of formula I having a double bond in the 5a(6)-positionand R₃ is other than hydrogen may be prepared by the process of BelgiumPat. No. 663,197. The compounds of formula I with no unsaturation andwith R₃ being hydrogen and R₁ being methyl may be prepared by theprocesses described in Belgium Pat. No. 663,197, U.S. Pat. No. 3,956,316and No. 3,644,429 and J. Chem. Soc. 1949, p. 1855-1865 and J. Chem.Soc., 1962, p. 1312-1313.

The saturated products of formula I wherein R₃ is hydrogen and R₁ isethyl may be prepared as described in Belgium Pat. No. 767,347 and thesaturated products wherein R₁ is methyl and R₃ is other than hydrogenmay be prepared by Belgium Pat. No. 663,197 and U.S. Pat. No. 3,496,199.

In the examples, the nomenclature used is derived from the followingnumbering system. ##STR25##

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 12α,3aβ,6-trimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-oneSTEP A:3a,6-dimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol

A mixture of 5.5 g of 3a,6-dimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-one,5.5 ml of ethylene glycol, 9 ml of ethyl orthoformate, 200 mg ofp-toluene sulfonic acid and 200 ml of benzene was refluxed undernitrogen for 3 hours and anhydrous sodium carbonate was added thereto.The mixture was washed with sodium hydroxide solution and was evaporatedto dryness. The residue was chromatographed over silica gel and elutedwith a 1-9 acetonehexane mixture to obtain 3.22 g of3a,6-dimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol.

STEP B:3aβ,6-dimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3-one

1.9 g of the product of Step A were oxidized with 6.37 g of pyridiniumdichromate in 19.5 ml of a dimethylformamide-methylene chloride mixtureat room temperature for 2 hours. The product was taken up in water andthe aqueous phase was extracted with ether. The organic phase wasevaporated to dryness and the residue was crystallized from hexane toobtain 1.235 g of an epimeric mixture of3aβ,6-dimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3-onemelting at 95° C.

NMR Spectrum (deuterochloroform): Peak at 0.85 ppm (methyl at 3a).

STEP C:2α,3aβ,6-trimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahyro-7H-benz(e)-inden-3-one

A solution was prepared under a nitrogen atmosphere at 0° C. of 0.17 mlof diisopropylamine and a hexane solution of 1.6M of butyllithium in 2ml of tetrahydrofuran in the presence of a bipyrydil crystal as a colorindicator and after 10 minutes, the red solution was admixed at 0° C.with a mixture of 276 mg of the product of Step B and 1 ml oftetrahydrofuran. The temperature was allowed to rise to room temperatureand after 20 minutes, 0.4 ml of methyl iodide was added to the mixture.The color of the mixture turned yellow and a precipitate rapidlyappeared. The mixture was poured into water and was extracted with etherto obtain 294 mg of a product melting at 110° C. The latter wascrystallized from a hexane-ether mixture to obtain 225 mg of2α,3aβ,6-trimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3-onemelting at 136° C.

NMR Spectrum (deuterochloroform): Peak at 0.87 ppm (3a-methyl).

STEP D:2α,3aβ,6-trimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol

130 mg of the product of Step C were reacted with 32 mg of lithiumaluminum hydride in ether at room temperature for 10 minutes and themixture was hydrolyzed with water and 15% sodium hydroxide. The mixturewas filtered and the filtrate was evaporated to dryness to obtain an oilof2α,3aβ,6-trimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol.

NMR Spectrum (deuterochloroform): Peaks at 0.72 ppm (3a methyl).

STEP E:2α,3aβ,6-trimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-one

A mixture of the product of Step D in aqueous acetone in the presence ofa few mg of p-toluene sulfonic acid was heated to reflux and cooled. Themixture was extracted with ether and the extract was chromatographedover silica gel. Elution with an 8-2 acetone-hexane mixture andcrystallization of the product from aqueous methanol yielded 60 mg of2α,3aβ,6-trimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3β-ol-7-onemelting at 139° C. and having a specific rotation of [α]_(D) ²⁵ =-51°(c=1% in chloroform).

NMR Spectrum (deuterochloroform): Peak at 0.90 ppm (3a methyl).

Analysis: C₁₆ H₂₄ O₂ : Calculated: %C, 77.37; %H, 9.74. Found: %C, 77.1%H, 9.6.

EXAMPLE 22β,3aβ6-trimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-oneSTEP A:2β,3aβ,6-trimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3-one

A mixture of 240 mg of the product of Step C of Example 1 in 2.6 ml 2Npotassium methanolate was refluxed for 90 minutes and was evaporated todryness. The residue was taken up in water and the aqueous phase wasextracted with ether to obtain a 1-1 mixture of 2α and 2β-isomers of thedesired compound. The mixture was chromatographed over silica gel andwas eluted with a 1-9 ethyl acetate-hexane mixture to obtain 110 mg of2β,3aβ,6-trimethyl-7,7-ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3-onein the form of an oil.

NMR Spectrum (deuterochloroform): Peak at 0.8 ppm (3a methyl).

STEP B:2β,3aβ,6-trimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-one

Using the product of Step D of Example 1, the 110 mg of the product ofStep A were reacted to obtain 2β,3aβ,6-trimethyl-7,7ethylenedioxy-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol which wasreacted as in Step E of exemple 1 to obtain 70 mg of2β,3aβ,6-trimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7-H-benz(e)-inden-3β-ol-7-onewhich melted at 81° C. after crystallization from an ether-hexanemixture. The product had a specific rotation of [α]_(D) ²⁵ =-32° (c=1%in chloroform).

Analysis: C₁₆ H₂₄ O₂ : Calculated: %C, 77.37; %H, 9.74. Found: %C, 77.2;%H, 9.8.

EXAMPLE 33aβ,6-diethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3.beta.-ol-7-one

3.36 ml of an 0.8M of freshly prepared n-propyl magnesium bromide inether were added slowly at -60° C. to a solution of 500 mg of the δlactone of1β-acetoxy-4-(2'-carboxyethyl)-5-hydroxy-7a-ethyl-3a,4β,7,7a-tetrahydro-indanein 3.8 ml of anhydrous tetrahydrofuran and after one hour of reaction at-60° C., excess magnesium was destroyed by addition of water. Thetetrahydrofuran was evaporated and an aqueous saturated ammoniumchloride solution was added to the mixture. The mixture was extractedwith ether and the ether phase was dried and evaporated to dryness. Theresidue was admixed with 3.7 ml of 2N potassium methanolate and themixture was refluxed for one hour and was neutralized with acetic acid.The mixture was evaporated to dryness and the residue was taken up inwater. The aqueous phase was extracted with methylene chloride and theorganic phase was evaporated to dryness to obtain 470 mg of raw product.The latter was crystallized from an acetone-hexane mixture to obtain 100mg of3aβ,6-diethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3.beta.-ol-7-onemelting at 131.5° C. and having a specific rotation of [α]_(D) ²⁵ =-58°(c=1% in methanol).

Analysis: C₁₇ H₂₆ O₂ : Calculated: %C, 77.82; %H, 9.99. Found: %C, 78.0;%H, 10.0.

EXAMPLE 43aβ-ethyl-6-propyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-one

Using the procedure of Example 3, 500 mg of δ lactone of1β-acetoxy-4-(2'-carboxyethyl)-5-hydroxy-7a-ethyl-3a,4β,7,7a-tetrahydroindaneand n-butyl magnesium bromide were reacted to obtain 220 mg of residuewhich was crystallized from acetone to obtain 105 mg of3aβ-ethyl-6-propyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-onemelting at 127° C. and having a specific rotation of [α]_(D) ²⁵ =-55°(c=1% in methanol).

Analysis: C₁₈ H₂₈ O₂ : Calculated: %C, 78.21; %H, 10.21. Found: %C,78.4; %H, 10.1.

EXAMPLE 53aβ,ethyl-6-methyl-3β-acetoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

Acetic anhydride and a solution of3aβ-ethyl-6-methyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-onein pyridine were reacted and the resulting product was crystallized fromaqueous methanol to obtain3β,ethyl-6-methyl-3β-acetoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onemelting at 99° C.

EXAMPLE 63aβ-ethyl-6-methyl-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-3.beta.-ol-7-oneSTEP A:3aβ-ethyl-5-bromo-6-methyl-3β-acetoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

A mixture of 210 mg of the product of Example 5, 0.72 ml of aceticanhydride and 10 mg of p-toluene sulfonic acid stood for 16 hours andthen 0.3 ml of acetic acid and 0.43 ml of water were added thereto. Themixture stood at room temperature for 2 hours and was then cooled to 5°C. and mixed with 130 mg of N-bromosuccinimide. The mixture was stirredfor 2 hours and 0.72 ml of water were added thereto. The mixture wasfiltered to obtain 190 mg of3aβ-ethyl-5-bromo-6-methyl-3β-acetoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onemelting at ≃120° C.

STEP B:3aβ-ethyl-6-methyl-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-3.beta.-ol-7-one

A mixture of 190 mg of the product of Step A, 95 mg of lithium bromideand 47 mg of lithium carbonate in 4.5 ml of dimethylformamide wasdistilled for 30 minutes under nitrogen almost to dryness and was thencooled. 5 ml of water and 0.1 ml of acetic acid were added to themixture and the mixture was poured into water. The mixture was extractedwith methylene chloride and the organic phase was evaporated to drynessto obtain 128 mg of product. The latter was chromatographed over silicagel and was eluted with an acetone-hexane mixture to obtain3aβ-ethyl-6-methyl-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-3.beta.-ol-7-onemelting at 155° C. and having a specific rotation of [α]_(D) ²⁵ =-207°(c=1% in chloroform).

Analysis: C₁₆ H₂₂ O₂.0.5 ##STR26## Calculated: %C, 76.32; %H, 9.15.Found: %C, 76.65; %H, 9.3.

EXAMPLE 7 Butanoate of3aβ-methyl-6-ethyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahydro-1H-benz(e)-inden-3-yl

30 mg of 4-dimethylamino-pyridine were added to a solution of 0.75 g of3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-one,1.5 ml of butyric acid anhydride and 1.05 ml of dry triethylamine andthe mixture was stirred at room temperature for 2 hours and was pouredinto aqueous saturated sodium bicarbonate solution. The mixture wasstirred for 2 hours and was extracted with methylene chloride. Theorganic phase was washed with water, dried and evaporated to dryness toobtain 0.96 of an oil. The latter was chromatographed over silica geland was eluted with a 9-1 benzene-ethyl acetate mixture to obtainbutanoate of3aβ-methyl-6-ethyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahydro-1H-benz(e)-inden-3-yl.

Analysis: C₂₀ H₃₀ O₃ : Calculated: %C, 75.43; %H, 9.49. Found: %C, 75.6;%H, 9.50.

NMR Spectrum (deuterochloroform): Peaks at 0.9 ppm (t) (hydrogens ofmethyl of CH₃ --CH₂ --); at 0.97 ppm (hydrogens of 3a methyl); at 0.97ppm (t) (hydrogens of methyl of CH₃ --CH₂ --); at 4.68 ppm (t)(3α-hydrogen) (J=8 Hz.

EXAMPLE 83-methoxy-methoxy-3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

1 g of lithium carbonate and 1 ml of methoxymethyl chloride were addedat room temperature to a solution of 2 g of3a-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3.beta.-ol-7-onein 20 ml of dry dimethylformamide and then 1 g of lithium carbonate and1 ml of methoxymethyl chloride were successively added 2,4 and 5 hourslater. Another 1 ml of methoxymethyl chloride was added to the mixtureat the 6th hour and one hour later, the mixture was poured into amixture of 40 ml of aqueous saturated sodium bicarbonate solution and 80ml of water. The mixture was extracted with ethyl acetate and theorganic phase was washed with water, dried and evaporated to dryness.The 2.4 g of oil residue were chromatographed over silica gel and elutedwith a 7-3 benzene-ethyl acetate mixture to obtain 1.6 g of3-methoxy-methoxy-3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one with an Rf=0.48.

Analysis: C₁₈ H₂₈ O₃ : Calculated: %C, 73.93; %H, 9.65. Found: %C, 73.9;%H, 9.7.

NMR Spectrum (deuterochloroform): Peaks at 0.9 ppm (t) (hydrogens ofmethyl of 6--CH₃ --CH₂); at 0.96 ppm (hydrogens of 3a-methyl); at 3.58ppm (t) (3-hydrogen); at 4.06 ppm (hydrogens of CH₃ --O); at 4.68 ppm(hydrogens of methylene of CH₃ --O--CH₂ --)

EXAMPLE 93aβ-methyl-3-(2-propenyloxy)-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-oneSTEP A:1,2,3,3a,4,6,8,9,9a,9b-decahydro-6β-ethyl-3aβ-methylspiro-[7H-benz(e)-indene-7,2'-(1,3)-dioxolane]-3β-ol

A suspension of 4 g of3a-methyl-6β-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-one,40 ml of ethyleneglycol and 4 ml of ethyl orthoformate was heated to 75°C. and 20 mg of p-toluene sulfonic acid were added thereto all at once.The mixture was stirred for 3 hours and another 20 mg of p-toluenesulfonic acid were added. The mixture was heated at 75° C. for one hourand was then cooled. 1 ml of triethylamine was added to the mixturewhich was then poured into 80 ml of water. The mixture was extractedwith ethyl acetate and the organic phase was washed with water, driedand evaporated to dryness. The 4.6 g of resin residue werechromatographed over silica gel and eluted with a 1-1 cyclohexane-ethylacetate mixture to obtain 3.4 g of1,2,3,3a,4,6,8,9,9a,9b-decahydro-6β-ethyl-3aβ-methyl-spiro-[7H-benz(e)-indene-7,2'-(1,3)-dioxolane]-3β-ol melting at 148° C.

STEP B:3aβ-methyl-3-(2-propenyloxy)-6β-ethyl-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7,7-ethylenedioxy-7H-benz(e)-indene

0.489 g of a 50% suspension of sodium hydride in oil were added to asolution of 3 g of the product of Step A in 30 ml of tetrahydrofuran andthe mixture was held in an oil bath at 45° C. 3 ml of allyl bromide wereadded to the mixture which was heated for 3 hours at 45° C. after whichanother 3 ml of allyl bromide were added. The mixture was heated foranother 3 hours at 45° C. and was refluxed for one hour and cooled. Themixture was poured into 300 ml of aqueous saturated sodium bicarbonatesolution and the mixture was extracted with ethyl acetate. The organicphase was washed with water, dried and evaporated to dryness to obtain3.5 g of an oil residue. 250 mg of the product were chromatographed oversilica gel and eluted with a 7-3 benzene-ethyl acetate mixture to obtain0.16 g of 3aβ-methyl-3-(2-propenyloxy)-6β-ethyl-1,2,3,3a,4,6,8,9,9a,9b-decahydro-7,7-ethylenedioxy-7H-benz(e)-indene.

NMR Spectrum (deuterochloroform): Peaks at 0.76 ppm (hydrogens of3a-methyl); at 0.81 ppm (t) (hydrogens of terminal CH₃ of 6-ethyl) (J=7Hz); at 3.5 ppm (3α-hydrogen); at 4 ppm (m) (hydrogens of --O--CH₂--CH═CH₂); at 5.66 ppm (m) (hydrogen of --O--CH₂ --CH═CH₂).

STEP C:3aβ-methyl-3-(2-propenyloxy)-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

A solution of 3 g of the product of Step B, 18 ml of 2N aqueoushydrochloric acid and 450 ml of methanol was stirred at room temperaturefor 4 hours and the methanol was evaporated. The residue was taken up in45 ml of water and the mixture was extracted with ethyl acetate. Theorganic phase was washed with aqueous sodium bicarbonate solution, withwater, dried and evaporated to dryness. The 2.5 g of oil residue werechromatographed over silica gel and eluted with a 7-3 benzene-ethylacetate mixture to obtain 1.64 g of3aβ-methyl-3-(2-propenyloxy)-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one.

Analysis: C₁₉ H₂₈ O₂ : Calculated: %C, 79.12; %H, 9.78. Found: %C, 79.3;%H, 9.9.

NMR Spectrum (deuterochloroform): Peaks at 0.91 ppm (t) (hydrogens ofterminal CH₃ at 6) (J=7 Hz); at 0.96 ppm (hydrogens of 3a methyl); at3.43 ppm (t) (3α-hydrogen); at 5.26 ppm (m) (hydrogens of methylene of--CH═CH₂); at 5.98 ppm (m) (hydrogen of --CH═CH₂).

EXAMPLE 103aβ-methyl-3β-acetoxy-6-propyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

9.6 ml of an ether solution of 0.8M of freshly prepared n-butylmagnesium bromide were added at -60° C. over 30 minutes to a solution of1.35 g of the γ-lactone of1β-acetoxy-4-(2'-carboxyethyl)-5-hydroxy-7aβ-methyl-3aα,4.beta.,7,7a-tetrahydro-indanein 10 ml of anhydrous tetrahydrofuran and after stirring at -60° C. forone hour, 15 ml of water were added thereto to destroy excess magnesiumreactant. The mixture was evaporated to dryness and the residue wasadded to aqueous saturated ammonium chloride solution. The mixture wasextracted with ether and the organic phase was dried and evaporated todryness to obtain 1.43 g of3aβ-methyl-3β-acetoxy-6-propyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one.

EXAMPLE 113aβ,6-dimethyl-3β-acetoxy-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-7-oneSTEP A:3aβ,6-dimethyl-5-bromo-3β-acetoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

A mixture of 23.4 g of3aβ,6-dimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3β-ol-7-one, 100 ml of acetic anhydride and 1 g of p-toluenesulfonic acid was stirred and then allowed to stand at about 20° C. for16 hours. 40 ml of acetic acid and 60 ml of water were added to themixture at less than 30° C. and was then held at 5° C. for 2 hours. 17.8g of N-bromo-succinimide were added to the mixture over 10 minutes whilekeeping the temperature below 15° C. and the mixture was stirred for 30minutes and poured into 100 ml of water. The mixture was vacuum filteredand the product was washed with ethanol containing 40% of water thenwith ethanol and dried at 40° C. to obtain 26.3 g of3aβ,6-dimethyl-5-bromo-3β-acetoxy-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one which aftercrystallization from a methylene chlorideisopropyl ether mixture meltedat 140° C. and had a specific rotation of [α]_(D) ²⁵ =+226°±3° (c=1% inchloroform).

Analysis: C₁₇ H₂₃ O₃ Br: Calculated: %C, 57.47; %H, 6.52. Found: %C,57.8; %H, 6.7.

STEP B:3aβ,6-dimethyl-3β-acetoxy-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-7-one

A mixture of 2 g of lithium bromide, 1 g of lithium carbonate and 90 mlof dimethylformamide was distilled to remove 10 ml for drying and 4 g ofthe product of Step A were added thereto. The mixture was evaporated toabout 50 ml in 30 minutes and was cooled and 100 ml of water and then 2ml of acetic acid were added to the mixture which was poured into water.The mixture was extracted 3 times with methylene chloride and thecombined organic phases were washed with water, dried and evaporated todryness. The residue was chromatographed over silica gel and eluted with95-5 methylene chloride-isopropyl ether mixture. The product wascrystallized from petroleum ether to obtain 2.32 g of3aβ,6-dimethyl-3β-acetoxy-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-7-onemelting at 75° C. and having a specific rotation of [α]_(D) ²⁵=-143°±1.5° (c=1% in chloroform).

Analysis: C₁₇ H₂₂ O₃ : Calculated: %C, 74.42; %H, 8.08. Found: %C, 74.5;%H, 8.2.

EXAMPLE 123aβ,6-dimethyl-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-3β-ol-7-one

A mixture of 15.2 g of the product of Example 11, 152 ml of ethanol and55 ml of 2N sodium hydroxide solution stood at 20° C. for 2 hours andthen 600 ml of water were slowly added thereto. The mixture was vacuumfiltered and the product was washed with water and dried to obtain 11.6g of product. The latter was dissolved in methylene chloride and thesolution was treated with activated carbon and isopropyl ether wasadded. The mixture was concentrated under reduced pressure at about 30°C. and was vacuum filtered. The product was washed with isopropyl etherand dried to obtain 11.3 g of3aβ,6-dimethyl-1,2,3,3a,8,9,9a,9b-octahydro-7H-benz(e)-inden-3β-ol-7-onemelting at 156° C. and having a specific rotation of [α]_(D) ²⁵=-188°±2° (c=1% in chloroform).

Analysis: C₁₅ H₂₀ O₂ : Calculated: %C, 77.55; %H, 8.68. Found: %C, 77.5;%H, 8.7.

EXAMPLE 133β-acetoxy-3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

12 ml of pure acetic anhydride were rapidly added to a solution of 6 gof3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-onein 24 ml of pyridine and the solution was held at room temperature for15 hours. The mixture was poured into 240 ml of water and the mixturewas filtered. The product was washed with water and dried to obtain 6.8g of product which was crystallized from hexane to obtain 6.5 g of3β-acetoxy-3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onemelting at 90° C.

Analysis: C₁₈ H₂₆ O₃ : Calculated: %C, 74.44; %H, 9.02. Found: %C, 74.4;%H, 9.1.

NMR Spectrum (deuterochloroform): Peaks at 0.91 ppm (t) (hydrogens ofCH₃ of 6-ethyl) (J=8 Hz); at 0.97 ppm (hydrogens of 3a-methyl); at 2.06ppm (hydrogens of acetoxy); at 4.65 ppm (t) (3α-hydrogen) (J=8 Hz).

EXAMPLE 143aβ-methyl-3β-propionyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

Using the procedure of Example 13, 1 g of3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-oneand 2 ml of propionic anhydride were reacted and the product wasextracted with ether. The organic phase was washed with aqueoussaturated sodium bicarbonate solution, with water, dried and evaporatedto dryness. The residue was chromatographed over silica gel and waseluted with a 9-1 benzene-ethyl acetate mixture to obtain 1.08 g of3aβ-methyl-3β-propionyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onemelting at 50° C. and having a specific rotation of [α]_(D) ²⁵ =-28°±2°(c=0.4% in ethanol).

Analysis: C₁₉ H₂₈ O₃ : Calculated: %C, 74.96; %H; 9.27. Found: %C, 75.0;%H, 9.2.

EXAMPLE 153aβ-methyl-3β-valeryloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

Using the procedure of Example 14, 0.5 g of3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-oneand 1 ml of valeryl anhydride were reacted to obtain 0.590 g of3aβ-methyl-3β-valeryloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onewith a specific rotation of [α]_(D) ²⁵ =-18°±2° (c=0.5% in ethanol).

Analysis: C₂₁ H₃₂ O₃ : Calculated: %C, 75.86; %H, 9.70. Found: %C, 76.0;%H, 9.9.

EXAMPLE 163aβ-methyl-3β-hexanoyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

Using the procedure of Example 14, 1 g of3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-oneand 2 ml of caproic anhydride were reacted to obtain 0.7 g of3aβ-methyl-3β-hexanoyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onewith a specific rotation of [α]_(D) ²⁵ =-15.5° (c=0.5% in ethanol).

Analysis: C₂₂ H₃₄ O₃ : Calculated: %C, 76.25; %H, 9.89. Found: %C, 76.3;%H, 9.9.

EXAMPLE 173aβ-methyl-3β-(pyridin-3-yl)-carbonyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one

1.95 g of nicotinic acid chloride hydrochloride were added with stirringunder an inert atmosphere to 15 ml of anhydrous pyridine and then 2.48 gof3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-onewere added to the mixture. The mixture was heated at 90°-95° C. for 21/2hours, was cooled and poured into an ice-water mixture. The mixture wasfiltered and the product was washed with water and dried. The filtratewas extracted with ethyl acetate and the organic phase was washed withwater, dried and evaporated to dryness. The filter product and theresidue were combined and chromatographed over silica gel. Elution witha 98-2 chloroform-methanol mixture yielded 2.75 g of3aβ-methyl-3β-(pyridin-3-yl)-carbonyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-onemelting at 134° C. and having a specific rotation of [α]_(D) ²⁵=+46.5°±2° (c=0.75% in ethanol).

Analysis: C₂₂ H₂₇ NO₃ : Calculated: %C, 74.75; %H, 7.70; %N, 3.96.Found: %C, 74.9; %H, 7.8; %N; 3.9.

EXAMPLE 18

A pomade for cutaneous application was prepared containing 50 mg of theproduct of Example 3 and sufficient excipient of mineral oil, propyleneglycol and petrolatum designed as a mixture of semisolid hydrocarbonsobtained from petroleum (See USP.XX) for a final weight of 1 g.

A gel composition was prepared containing 50 mg of the product ofExample 3 and sufficient excipient of alcohol, carbopol, propyleneglycol, water and diisopropanol amine for a total weight of 1 g.

Gelules were prepared containing 50 mg of the product of Example 3 andsufficient excipient of magnesium stearate, lactose and starch for afinal weight of 400 mg.

PHARMACOLOGICAL DATA

In the following tests, product A is3aβ,6-dimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3.beta.-ol-7-onedescribed in Belgium Patent No. 663,197, product B is3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-onedescribed in French Patent No. 1,359,675 and product C is3aβ-ethyl-6-methyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-3β-ol-7-onedescribed in J. Org. Chem., Vol. 34(1) (1969), P 107-112 and are withinthe scope of formula I.

A. Measure of Interaction with Androgen Receptor

The prostates of adult male rats weighing 200 g castrated 24 hoursearlier were homogenized at 0° C. in a buffered T.S. consisting of 10 mMTris and 0.25M of saccharose with a pH of 7.4 at a rate of 1 g ofprostate per 5 ml of buffered solution. The homogenate was centrifugedat 105,000 g for 60 minutes in an ultracentrifuge and the surnageant wascalled cytosol. Samples of 125 μl of cytosol were incubated for 30minutes or 24 hours at 0° C. in the presence of 5 nM of(3H)-testosterone in the absence (Bo) or in the presence (B) ofincreasing concentrations of cold test products. After the incubation.100 μl of the incubate were stirred with 100 μl of a suspension of 1.25%of Norit A (carbon) and 0.625% of Dextran T80 for 10 minutes at 0° to 4°C. in a microtiter plate and the mixture was centrifuged at 800 g for 10minutes at 0° to 4° C. The radioactivity contained in the samples of 100μl of surnagent was measured by liquid scintillation and the value ofthe ratio of B/Bo was graphically represented as a function ofconcentration of cold product added. The concentration of test productnecessary to inhibit by 50% the fixation of (3H)-testosterone or CI₅₀was graphically determined. The ratio ##EQU1## gives the affinity valuerelative to the test product for androgen receptor. Previous studiesshowed that the relative affinity for a product diminished when theincubation temperature increased and that the product was deemed apotential antihormone [TIPS, August, 1980, p. 324 and Advances inPharmacology and Therapeutics, Vol. 1 receptors, p. 259 (1979)]. Theresults are reported Table I.

                                      TABLE I                                     __________________________________________________________________________              Product                                                                            Product                                                                            Product                                                                            Product                                                                            Product                                                                            Product                                                                            Product                                                                            Product                                    A    B    C    of Ex. 1                                                                           of Ex. 2                                                                           of Ex. 3                                                                           of Ex. 4                                                                           of Ex. 12                        __________________________________________________________________________    % Relative affinity                                                                     46   7,2  11,4 7,2  17   9,7  2,3  73                               with 30 minutes                                                               incubation                                                                    % Relative affinity                                                                      4   0,8  5    1,3  1,7  1,2  0,3  8,4                              with 24 hours                                                                 incubation                                                                    __________________________________________________________________________

B. In Vivo Study with Costovertebral Organ of Hamsters

Male golden hamsters weighing 100 to 110 g castrated 7 days earlierreceived a subcutaneous injection of 125 μg per day and per animal oftestosterone propionate in 0.2 ml of a sesame oil solution containing0.5% of benzyl alcohol. One group of animals received also a treatmentby topical application of an ethanol solution of the test compound onthe right costovertebral organ and the left costovertebral organreceived only ethanol. The treatment lasted for 8 days and 24 hoursafter the last, the costovertebral organs and the prostate were removedand weighed. Control animals received only solvents and the results arereported in Table II.

                  TABLE II                                                        ______________________________________                                        Daily    Control Gland                                                                              Treated Gland                                                                             Prostate                                    Treatments                                                                             in mg        in mg       in mg                                       ______________________________________                                        Controls  6,3 ± 0,7                                                                               6,4 ± 0,5                                                                             17,8 ± 2,7                               Testosterone                                                                           35,8 ± 5,0                                                                              33,91 ± 2,9                                                                            79,5 ± 5,5                               Propionate                                                                    0,125 μg/day                                                               Testosterone                                                                           41,8 ± 5,2                                                                              17,1 ± 2,2                                                                             80,1 ± 9,3                               Propionate                                                                    125 μg/day                                                                 + Product B                                                                   1 mg/day                                                                      ______________________________________                                    

Local applications of product B to the right costovertebral organ causeda 61% inhibition in the weight increase of the organ. Product B did notantagonize the effect of testosterone propionate on the untreated glandor the prostate indicating that the compound does not have a systemiceffect.

The study was repeated with female hamsters to test the antiandrogenicactivity of the compounds of Examples 7 and 13 at a dose of 5 mg/day andthe results are reported in Table III.

                  TABLE III                                                       ______________________________________                                                          Control   Treated                                                             Gland     Gland                                             Daily Treatment   in mg     in mg                                             ______________________________________                                        Control            3,0 ± 0,4                                                                           3,4 ± 0,4                                      Testosterone      15,8 ± 1,0                                                                           14,9 ± 1,1                                     Propionate                                                                    0,125 μg/day                                                               Testosterone       9,5 ± 0,8                                                                           4,5 ± 0,4                                      Propionate                                                                    0,125 μg/day                                                               + Product of Example 7                                                        5 mg/day                                                                      Testosterone      10,8 ± 2,1                                                                           3,9 ± 0,4                                      Propionate                                                                    0,125 μg/day                                                               + Product of Example 13                                                       5 mg/day                                                                      ______________________________________                                    

Topical application of the product of Example 7 to the rightcostovertebral organ caused a 90% inhibition of the weight increase ofthe organ while the product of Example 13 caused a 95.6% inhibition.

The test was repeated on female hamsters to determine the antiandrogenicactivity of the compounds of Examples 13 to 17 at 1 mg/day and theresults are reported in Table IV.

                  TABLE IV                                                        ______________________________________                                                   Control    Treated                                                            Gland      Gland     % inhibition of                               Daily Treatment                                                                          in mg      in mg     weight increase                               ______________________________________                                        Control    3,3 ± 0,6                                                                             3,3 ± 0,6                                            Testosterone                                                                             11,0 ± 2,0                                                                            10,2 ± 0,6                                           Propionate                                                                    0,125 μg/day                                                               Testosterone                                                                             9,9 ± 1,6                                                                             6,0 ± 0,2                                                                            61%                                           Propionate +                                                                  Product of Ex. 13                                                             1 mg/day                                                                      Testosterone                                                                             8,4 ± 0,7                                                                             4,9 ± 0,3                                                                            77%                                           Propionate +                                                                  Product of Ex. 14                                                             1 mg/day                                                                      Testosterone                                                                             7,1 ± 1,0                                                                             5,3 ± 0,6                                                                            71%                                           Propionate +                                                                  Product of Ex. 15                                                             1 mg/day                                                                      Testosterone                                                                             8,5 ± 0,5                                                                             5,6 ± 0,8                                                                            67%                                           Propionate +                                                                  Product of Ex. 16                                                             1 mg/day                                                                      Testosterone                                                                             9,6 ± 1,1                                                                             8,2 ± 0,9                                                                            29%                                           Propionate +                                                                  Product of Ex. 17                                                             1 mg/day                                                                      ______________________________________                                    

C. Acute Toxicity

Five male mice weighing 18 to 20 g received an intraperitoneal or oraladministration of decreasing doses of product B in aqueous solutioncontaining 0.25% of carboxymethyl cellulose and 0.2% of Tween at 1000,600 or 400 mg/kg and the number of dead mice was determined on the 7thday. The DL_(o) or the more elevated dose at which no mortality wasobserved was determined to be 400 mg/kg intraperitoneally and 1000 mg/kgorally for product B.

Various modifications of the products and processes of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What is claimed is:
 1. A compound of the formula ##STR27## wherein R₂ isselected from the group consisting of hydrogen, formyl and acyl of anorganic carboxylic acid of 2 to 18 carbon atoms, R₄ is selected from thegroup consisting of hydrogen and methyl and the wavy line indicates thatR₄ may be in the α- or β-position.
 2. A compound of claim 1 wherein R₂is acyl of an organic carboxylic acid selected from the group consistingof propionic acid, butyric acid, valeric acid and hexanoic acid.
 3. Acompound of claim 1 wherein R₁ is hydrogen.
 4. A compound of claim 1selected from the group consisting of butanoate of3αβ-methyl-6-ethyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahydro-1H-benz(e)-inden-3-yland3αβ-methyl-3β-hexanoyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-7-one.
 5. An antiandrogenic composition comprising anantiandrogenically effective amount of a compound of the formula##STR28## wherein R is ethyl, R₁ is methyl, R₂ is selected from thegroup consisting of hydrogen, formyl and acyl of an organic carboxylicacid of 2 to 18 carbon atoms, R₃ is hydrogen, R₄ is selected from thegroup consisting of hydrogen and alkyl of 1 to 4 carbon atoms, thedotted lines indicate no double bond between the 4(5) carbon atoms and adouble bond between 5a(6) carbon atoms and the wavy line indicates thatR₄ may be in the α- or β-position and a non-toxic, pharmaceuticalcarrier.
 6. A composition of claim 1 wherein R₂ is selected from thegroup consisting of hydrogen and acyl of an organic carboxylic acidselected from the group consisting of propionic acid, butyric acid,valeric acid and hexanoic acid.
 7. A composition of claim 1 wherein R₄is hydrogen.
 8. A composition of claim 1 wherein the active compound isselected from the group consisting of3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9,a,9b-decahydro-7H-benz(e)-indene-3β-ol-7-one;butanoate of3aβ-methyl-6-ethyl-7-oxo-1,2,3,3a,4,5,8,9,9,a,9b-decahydro-1H-benz(e)-inden-3-yland3aβ-methyl-3β-hexanoyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9,a9b-decahydro-7H-benz(e)inden-7-one.
 9. A composition of claim 1 wherein the active compound is3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e) indene3β-ol-7-one.
 10. A method of inducing antiandrogenic activity inwarm-blooded animals comprising administering to warm-blooded animals anantiandrogenically effective amount of a compound of the formula##STR29## wherein R₂ is selected from the group consisting of hydrogen,formyl and acyl of an organic carboxylic acid of 2 to 18 carbon atoms,R₄ is selected from the group consisting of hydrogen and methyl and thewavy line indicates that R₄ may be in the α- or β-position.
 11. Themethod of claim 10 wherein the compound of formula I, R₂ is selectedfrom the group consisting of hydrogen and acyl of an organic carboxylicacid selected from the group consisting of propionic acid, butyric acid,valeric acid and hexanoic acid.
 12. The method of claim 10 wherein inthe compound of formula I, R₄ is hydrogen.
 13. The method of claim 10wherein the active compound is selected from the group consisting of3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-indene-3β-ol-7-one;butanoate of3aβ-methyl-6-ethyl-7-oxo-1,2,3,3a,4,5,8,9,9a,9b-decahydro-1H-benz(e)-inden-3-yland3aβ-methyl-3β-hexanoyloxy-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)-inden-7-one.14. A method of claim 10 wherein the active compound is3aβ-methyl-6-ethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)iden-3β-ol-7-one.